Research Effort to Block Amino Acid Impact on PKU Brain Function

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Dr. Michael Gibson, Professor and Chair of The Clinical Pharmacology Unit at Washington State University, explains his novel research effort trying to understand ways to block the transport of the amino acid, Phenylalanine, that has a negative impact on Phenylketonuria (PKU) brain function. He shares his hope that this National PKU Alliance-funded research may help to identify a compound that could liberalize the diet for PKU patients.

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Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Kevin Alexander:

Hello.  I'm Kevin Alexander, an adult living with PKU and bringing you the latest information and news about PKU, both patient stories, but also, today, we're going to share a little bit about some of the latest research in the PKU community.  And today I'm joined by Dr. Mike Gibson with Washington State University. 

First of all, Dr. Gibson, just, please give a brief introduction of yourself and the type of research that you do, concerning PKU. 

Dr. Gibson:

Thanks for the opportunity, Kevin.  I've been involved in research in inborn errors of metabolism, for the last 30 years.  I took my doctoral degree, actually, in chemistry, but also, really, in genetics with Dr. Bill Nyhan, UC San Diego.  And I've been working on various genetic disorders, inborn errors in metabolism for the last 30 years, as I said. 

I got interested in the PKU area in about the last two or three years, thinking about alternative ways to approach the treatment of that disorder, and especially an approach that is pharmacologically driven, in an attempt to find a compound, a nonphysiologic amino acid that can be given to patients, that could potentially block the majority of the transport of phenylalanine from the peripheral circulation, the blood, into the brain, and specifically block phenylalanine.  That's our goal and our research, that's gratefully funded by the National PKU Alliance. 

Kevin Alexander:

For those of us connected in the PKU community we understand that today, as it stands today, the foundation of the PKU diet is your formula intake combined with low-protein diet.  I guess, in layman's terms, what could this research potentially do to potentially change our understanding of treatment options for PKU? 

Dr. Gibson:

Well, the objective for this is, most of the pathology or sort of the disease state that's been thought about in terms of PKU, and other, what we call large neutral amino acid arenas, also like maple syrup urine disease, most of the pathology, probably, occurs in the brain, and so that is driven by high levels of phenylalaline in the brain. 

And so, what this research could, potentially, do is, certainly, relax the dietary restrictions for patients.  In other words, you could titrate up or increase your protein intake.  If you have an inhibitor, a compound that you can take daily, or twice daily, or three times daily, that would block a lot of the transported phenylalaline into the brain, then the goal would be, and the outcome would be, that you could really liberalize the diet of these patients, and they can really get closer to a more, lack of a better term, normal protein intake diet.  That's the objective. 

Kevin Alexander:

The goal for this, obviously, and the foundation of this relates to how phenylalanine gets into the brain.  Just as a quick recap, there are some people in our audience who may not have a complete understanding of what happens to the body when phenylalanine is intake, a very detailed way, so briefly describe that process that happens, when the protein is entered into the body what happens, and how that gets to the brain, and how your research will prevent that. 

Dr. Gibson:

Dietary consumption of any protein of your food, in general, goes through the GI where it's broken down into free amino acids, and then, basically, into the circulation, into the blood stream.  You may have first-pass metabolism in the liver, but you also uptake most of your nutrition through the GI, through the gastrointestinal system.  There are receptors in the GI which are specific for the large neutral amino acids, and the large neutral amino acids include phenylalaline, but also tyrosine, tryptophan, the branch gene amino acids, etc. 

Once those are taken up into the blood they can be transported into the brain on a very specific enzyme transporter, called the large neutral amino acid transporter.  That moves the large neutrals from the periphery, which is the blood, into the brain, across what we call the blood-brain barrier.  The blood-brain barrier is essentially a series of capillaries that, really, restrict what can go into the brain, into the central nervous system, but that's why you have specific transporters, like the large neutral amino acid transporter. 

And so, what our goal there is, is to find a compound that has enough specificity for that transporter, for the large neutral amino acid transporter, that can selectively block phenylalaline movement into the brain but still allow a reasonably normal transport of the other large neutral amino acids, i.e., tyrosine, the branched chain amino acids, methionine, etc.  So that's the objective here. 

Kevin Alexander:

What do you think is going to be the overall benefit, not simply just from a dietary perspective.  The goal, obviously, is to get to a place where the diet can be liberalized more.  How do you think that's going to enhance a patient's life?  I mean, besides the obvious amount of being able to free up the types of foods that somebody can eat, what do you think it's going to do to the overall quality of life in general? 

Dr. Gibson:

The transport across the large neutral amino acid transport, from the periphery, the blood, into the brain, what we call the central nervous system, on this transporter, when you have high phenylalanine you,sort of, overwhelm that transporter.  In other words, phenylalaline moves on the transporter at the exclusion of other large neutral amino acids.  Some of these large neutral amino acids, for example, tryptophan and tyrosine, are the precursors of very, very important monoamine neurotransmitters in the brain. 

And what we also hope to be able to do is learn more about this transporter and be able to find out what levels of phenylalanine are the level that is dangerous for transport of other large neutral amino acids.  There's been a lot of speculation, over decades, that a lot of the pathology, or the disease state, is occurring because, even, at what might be considered controlled levels of phenylalaline on diet, which is on the order of 360 micromolar or lower, that even on those concentrations in the blood, you're still having some effect on the large neutral amino acid transporter of the brain, and that's excluding other important large neutrals, like tyrosine, like methionine, like tryptophan. 

We hope to, not only be able to liberalize the diet, but also to be able to explore the characteristics of this transporter, get a better feeling for it and understand what really are the true levels of phenylalaline that cause us trouble, with respect to other large neutral amino acids getting in the brain. 

Kevin Alexander:

Where exactly are you in the level of this research?  Where do we stand today?  I know any time you start talking about new treatments for PKU, people get very, very excited, but where exactly are you in the research process? 

Dr. Gibson:

Right.  I would say right now, and we've got other grant applications going on this approach, we are at the preclinical stage.  So what does that mean?  We are basically doing studies in a PKU mouse model.  I published one paper, we have another paper in progress, and we are looking at optimizing, finding the right compound to inhibit this transporter, so we're doing experiments in the animal model.

We are also honing in on a couple of compounds that seem very promising, and then we are now at a stage, also, of doing some toxicity studies.  And the objective of the toxicity studies are to see what happens in the animal in terms of blood chemistries, in terms of liver morphology, in terms of neurologic behavior, when you give high doses of these compounds.  And, thus far, we don't see any good evidence for adverse effects, for real toxicity, but we need a lot more data. 

The ultimate goal, of course, is to get this, one or two of our compounds, to what we call a phase zero trial, and phase zero, in clinical investigations, is basically, first in human, first time ever used in human.  Whether it be a normal individual, just to look at tolerability or toxicity or any adverse effects, but, hopefully, in this phase zero trial, to undertake intake in PKU patients.  And they would, almost certainly, have to be adult patients, because it would be—in a phase zero trial attempts to do them in children—and there are lots of PKU children—are usually frowned upon by IRBs, Institutional Review Boards.  So that's the ultimate goal is to get us to a phase zero trial. 

Kevin Alexander:

From a broad-level perspective, for this project, what's your ultimate hope?  I mean, obviously, this kind of research could have a profound impact on PKU.  Adults, children, families of PKU, can impact whole quality of lifestyle.  What's your overall hope for this project? 

Dr. Gibson:

My overall goal and hope is that we can develop a pharmacotherapy for PKU, a specific, targeted—and I wouldn't say drug but I would say a specific, targeted and hopefully it will be a nonphysiological amino acid.  And what I mean by that is these are amino acids that look like large neutral amino acids but are not normally synthesized, metabolized, formed in the body.  These compounds, that we're looking at, can't be metabolized.  They can block the transporter, and then they're excreted in the urine through the kidneys. 

And so our ultimate goal is to have a pharmacotherapy for PKU patients.  Long term, it may not completely liberalize the diet, but it could be a very, very helpful dietary intervention, let's say, in adolescents and adults, that would be experiencing trouble in a lot of challenges, anxieties, etc., with maintaining a very restricted protein diet, and that's kind of the long-term objective. 

Kevin Alexander:

Well, thank you so much, Dr. Gibson, for joining us and talking with us about your research.  It's always fascinating to hear some of the latest information and the latest research into PKU, and please keep us updated in the future and let us know how the progress on this project proceeds. 

Dr. Gibson:

Thanks very much.  It's been my pleasure. 

Kevin Alexander:

Again, I'm Kevin Alexander, an adult living with PKU, bringing you the latest news and information related to PKU.  And remember, knowledge can be the best medicine of all. 

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.


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